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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 27  |  Issue : 2  |  Page : 395-400

Endogenous secretory receptor of advanced glycated end products of type II diabetic and hypertensive patients


1 Department of Medical Biochemistry, Faculty of Medicine, Menofia University, Menofia, Egypt
2 Department of Cardiology, Faculty of Medicine, Menofia University, Menofia, Egypt

Date of Submission14-Jul-2013
Date of Acceptance10-Oct-2013
Date of Web Publication26-Sep-2014

Correspondence Address:
Amany Mohammed Salah El-Din Wahb
MBBCh, Medical Biochemistry Department, Faculty of Medicine, Menofia University, Quesna, Menofia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.141714

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  Abstract 

Objective
The aim of this study was to examine the role of the endogenous secretory receptor for advanced glycation end products (esRAGE) as a biochemical marker for hypertensive patients with type II diabetes mellitus.
Background
Advanced glycation end products may cause vascular stiffening by forming cross-links through the collagen molecule or by interaction with their cellular transductional receptor [receptor for advanced glycation end products (RAGE)]. A secreted isoform of RAGE, termed endogenous secretory receptor for advanced glycation end products, may contribute toward the removal/detoxification of advanced glycation end products by acting as a decoy. This work aimed to study the role of esRAGE in hypertensive and diabetic patients.
Participants and methods
This study included 60 patients (20 patients with type II diabetes mellitus, 20 hypertensive patients, and 20 hypertensive type II diabetic patients) and 20 healthy individuals as a control group. The patients were recruited from the Cardiology Department, Menofia University Hospital. The studied participants were subjected to a full assessment of history, clinical examination (including measurement of blood pressure), and laboratory investigations including measurement of fasting blood glucose, lipid profile, urea, and creatinine measured using the enzymatic colorimetric method and esRAGE determined by the enzyme-linked immunosorbent assay measured by the ELISA technique.
Results
The results of the present study showed that the levels of serum esRAGE were significantly lower in all patient groups compared with the control group (P<0.001). esRAGE levels were also significantly lower in type II diabetic hypertensive patients than in hypertensive or diabetic patients alone (P<0.001). In the patient group, there was a significantly negative correlation between esRAGE and each of systolic and diastolic blood pressure, triacylglycerol, total cholesterol, and low-density lipoprotein cholesterol, whereas a significant positive correlation was found with high-density lipoprotein cholesterol.
Conclusion
esRAGE may be a novel and potential protective factor for essential hypertension and type II diabetic patients.

Keywords: Advanced glycation end products, endogenous secretory receptors for advanced glycation end products, essential hypertension, type II diabetes mellitus


How to cite this article:
Ghanayem NM, Aziz WF, El-Ghobashi YA, El-Shazly RM, El-Din Wahb AM. Endogenous secretory receptor of advanced glycated end products of type II diabetic and hypertensive patients. Menoufia Med J 2014;27:395-400

How to cite this URL:
Ghanayem NM, Aziz WF, El-Ghobashi YA, El-Shazly RM, El-Din Wahb AM. Endogenous secretory receptor of advanced glycated end products of type II diabetic and hypertensive patients. Menoufia Med J [serial online] 2014 [cited 2020 Apr 6];27:395-400. Available from: http://www.mmj.eg.net/text.asp?2014/27/2/395/141714


  Introduction Top


Diabetes and hypertension are closely related diseases; thus, they are officially considered 'comorbidities'. Unfortunately, diabetes makes hypertension more difficult to treat and hypertension makes diabetes even more dangerous [1]. Type II diabetes mellitus comprises an array of dysfunctions resulting from a combination of resistance to insulin action and inadequate insulin secretion, which lead to hyperglycemia, and is consequently associated with microvascular (i.e. retinal, renal, and possibly neuropathic), macrovascular (i.e. coronary and peripheral vascular), and neuropathic (i.e. autonomic and peripheral) complications. Overall, about 35% of all patients with diabetes have high blood pressure [2]. Hyperglycemia leads to nonenzymatic glycation of proteins and lipids with the formation of advanced glycation end products (AGEs). The degree of AGE formation is considered to be dependent on both glucose concentration and the duration of disease [3]. Receptor for advanced glycation end products (RAGE) is known to be involved in microvascular complications in diabetes. RAGE is also strongly associated with macrovascular complications in diabetes through regulation of atherogenesis, angiogenic response, vascular injury, and inflammatory response [4]. Recently, a novel splice variant of RAGE mRNA coding for a C-truncated secreted isoform, termed endogenous secretory receptor for advanced glycation end products (esRAGE), was identified that consists of only the extracellular ligand-binding domain and lacks a transmembrane anchoring domain. This form is released in the plasma by several cell types, such as endothelial cells and leukocytes. Unlike cell-surface RAGE, which acts as a signal transduction receptor for AGEs, soluble RAGE (sRAGE) contributes toward the removal/detoxification of AGEs by acting as a decoy [5-6]. Thus, the AGE-RAGE system appears to play a central role in the development/progression of both diabetic microvascular and macrovascular complications. High levels of serum sRAGE are associated with a lower incidence of Alzheimer's disease, coronary artery disease, hypertension, and rheumatoid arthritis in nondiabetic patients. Also, serum sRAGE levels are associated inversely with components of the metabolic syndrome and atherosclerosis such as carotid intima-media thickness in diabetic patients [7].


  Participants and methods Top


This study was carried out at the Medical Biochemistry and Cardiology Departments, Faculty of Medicine, Menofia University. It included 80 participants classified into four groups: group 1 included 20 patients with essential hypertension with blood pressure higher than 140/90 mmHg, measured in three consecutive situations when the patients were relaxed, or patients on antihypertensive therapy (three men and 17 women). Their ages ranged between 24 and 62 years. Group 2 included 20 diabetic (type II diabetes mellitus) normotensive patients (two men and 18 women). Their ages ranged between 26 and 70 years. The diagnosis was made on the basis of the American Diabetes Association (ADA) diagnostic criteria for the diagnosis of diabetes mellitus [8]. Group 3 included 20 diabetic hypertensive patients (seven men and 13 women). Their ages ranged between 39 and 70 years. Group 4 included 20 age-matched and sex-matched healthy individuals who served as controls with normal fasting blood glucose (FBG) (eight men and 12 women). Their ages ranged between 25 and 70 years. Written informed consent was obtained from all the studied participants in accordance with the principles of the Ethical Committee of Menofia Faculty of Medicine. All the participants studied were subjected to a full assessment of history, complete clinical examination, including measurement of blood pressure, and laboratory investigations.

Sample collection

Venous blood (7 ml) was withdrawn from every fasting participant (12 h) and divided as follows:

  1. Two milliliters was collected into a tube containing fluoride for the measurement of FBG.
  2. Five milliliters was collected into a plain tube, centrifuged, and serum was used for the measurement of total cholesterol (Tchol) using the Spinreact kit (Spain), high-density lipoprotein cholesterol (HDLc) using the Human kit (Germany), triglyceride using the Spinreact kit, serum urea using Diamond urea kits (Germany), and creatinine using Diamond diagnostics international serum creatinine kits (UK), fetal bovine serum using the Spinreact kit; all were measured using the enzymatic colorimetric method [9-14] and low-density lipoprotein cholesterol (LDLc) was calculated according to Friedewald et al. [15]. Serum esRAGE were determined by the enzyme-linked immunosorbent assay technique using the Assay Human esRAGE ELISA kit (Japan) [5].


Statistical analysis

Results were analyzed statistically using statistical SPSS program version 16. Two types of statistics were calculated: descriptive statistics, for example, percentage, mean, and SD and analytic statistics, for example, the c2 -test. A two-tailed Student's t-test was used to compare quantitative data. Statistical significance was considered at the P value less than 0.05.


  Results Top


The study showed a nonsignificant statistical difference between the studied groups in age and sex [Table 1]. There was a significant statistical difference between groups 1 and 2 in FBG, and systolic and diastolic blood pressure, whereas there was a nonsignificant statistical difference between the groups in the other studied parameters [Table 2]. There was a significant statistical difference between groups 1 and 3 in the esRAGE, and systolic and diastolic blood pressure, whereas there was a nonsignificant statistical difference between the groups in the other studied parameters [Table 2]. There was a significant statistical difference between groups 1 and 4 in triglyceride, Tchol, HDLc, LDLc, esRAGE, and systolic and diastolic blood pressure, whereas there was a nonsignificant statistical difference between the groups in the other studied parameters [Table 2]. There was a significant statistical difference between groups 2 and 3 in the esRAGE, and systolic and diastolic blood pressure, whereas there was a nonsignificant statistical difference between the groups in the other studied parameters [Table 2]. There was a significant statistical difference between groups 2 and 4 in triglyceride, Tchol, HDLc, LDLc, esRAGE, and FBG, whereas there was a nonsignificant statistical difference between the groups in the other studied parameters [Table 2]. There was a significant statistical difference between groups 3 and 4 in triglyceride, Tchol, HDLc, LDLc, esRAGE, systolic and diastolic blood pressure, and FBG, whereas there was a nonsignificant statistical difference between the groups in the other studied parameters [Table 2]. There was a significant negative correlation between esRAGE and each of systolic and diastolic blood pressure, serum triglyceride, serum Tchol, and LDLc. A nonsignificant positive correlation existed between esRAGE and serum urea and a significant positive correlation existed with serum HDLc. There was a nonsignificant negative correlation with each of age, FBG, and serum creatinine when they were compared with the patient group [Table 3]. Stepwise multiple regression analyses were carried out for the patients. The factors associated significantly with serum esRAGE in coefficient analyses were included as variables. In model 1, systolic blood pressure, serum triglyceride, serum Tchol, and LDLc were selected as independent factors associated inversely with serum esRAGE, whereas serum HDLc was selected as an independent factor associated positively with serum esRAGE. In model 2, when diastolic blood pressure was excluded from the variables, serum triglyceride was found to be a significant independent factor associated inversely with serum esRAGE level. Serum HDLc was found to be an independent factor associated positively with serum esRAGE. Furthermore, in model 3, when systolic and diastolic blood pressure were excluded, triglyceride was found to be a significant independent factor associated inversely with serum esRAGE levels. Serum HDLc was found to be an independent factor associated positively with serum esRAGE [Table 4].
Table 1: Statistical comparison between the studied groups in age and sex

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Table 2: Statistical comparison of studied parameters between the studied groups

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Table 3: Correlation coefficient between esRAGE and some clinical and biochemical parameters in the patient group (N = 60)

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Table 4: Stepwise multivariate regression analyses of the factors associated with the plasma esRAGE in all patients (N = 60)

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  Discussion Top


Diabetes mellitus and essential hypertension are major challenges among individuals worldwide. They are a major threat to public health, rapidly reaching an epidemic scale, with the biggest impact on adults of working age in developing countries. This work aimed to study the role of esRAGE in hypertensive and diabetic patients. The present study showed that there was no significant difference among the studied groups in age, and sex. In this study, there was no significant statistical difference between the studied groups in serum urea and creatinine. This is in agreement with the results obtained by other studies [16]. In the present study, significantly higher levels of serum Tchol, triglyceride, and LDLc concentration were observed in hypertensive patients, diabetic patients, and hypertensive type II diabetic patients in comparison with the control group, whereas serum HDLc concentration was significantly lower in all patient groups in comparison with the healthy controls. This is in agreement with the results obtained by other studies [17],[18],[19],[20],[21]. Insulin resistance (IR) is characterized by inadequate glucose uptake in peripheral tissues at a given concentration of plasma insulin. It involves an impairment in the nonoxidative (glycolytic) pathways of intracellular glucose metabolism. Humans with essential hypertension and normotensive offspring of essential hypertensives have IR. Abnormalities in glucose metabolism exist in up to 80% of patients with essential hypertension [22]. Boden and Laakso [23] and Fried et al. [24] reported that IR at the level of adipose tissue may result in increased activity of hormone-sensitive lipase and therefore increased breakdown of stored triglycerides. It was shown that patients with IR have an increased expression of hepatic lipase, which acts on HDLc, resulting in smaller HDLc particles that are catabolized more rapidly by the kidney, leading to lower plasma HDLc. Also, an enzyme called endothelial lipase is upregulated in IR states [25]. Sorrentino [26] reported that patients with IR tend to have impaired fasting plasma glucose levels, which increases the prevalence of more atherogenic, LDLc particles. The other associated abnormalities include increased levels of triacylglycerol-rich lipoproteins along with low levels of HDLc. This study reported that serum esRAGE concentrations were significantly lower in the hypertensive group than in the control group. This is in agreement with the results obtained by others [27],[28]. Koyama et al. [4] showed by western blot that serum esRAGE concentrations were significantly lower in hypertensive patients. These results are in agreement with some reports that indicated that low esRAGE is associated with hypertension in diabetics and nondiabetics. This study reported that serum esRAGE concentrations were significantly lower in the type II diabetic patient group than the control group. This is in agreement with the results obtained by others [4],[28],[29]. The decrease in esRAGE in type II diabetes and obesity has been attributed to the beneficial role of esRAGE and its function as a decoy in capturing the circulating AGEs, preventing activation of the RAGE signaling pathway as it still has the V-ligand essential for ligand binding [29]. The decoy function theory is supported by an in-vitro study that showed that the treatment with sRAGE normalized the increases in most of the inflammatory markers in diabetic mice to those observed in age-matched, nondiabetic controls [30]. This study reported that serum esRAGE concentrations were significantly lower in the group of hypertensive patients with type II diabetes than the control group. This is in agreement with the results obtained by others [7,27]. The current study found that esRAGE was significantly higher in hypertensive patients than in hypertensive type II diabetic patients and esRAGE was significantly higher in diabetic patients than in hypertensive type II diabetic patients. This is in agreement with the results obtained by others [7],[27]. The newest version of the response-to-injury hypothesis emphasizes that atherosclerosis is a multifactorial inflammatory disease involving endothelial cells, vascular smooth muscle cells, mononuclear cells, growth factors, and cytokines [31]. In metabolic syndrome, also known as syndrome X or IR syndrome, primary IR is linked to a group of coexisting conditions including hypertension, dyslipidemias, diabetes, and atherosclerotic cardiovascular disease [32]. Components of the metabolic syndrome and the metabolic syndrome itself are also associated with measures of inflammation, such as increased concentrations of C-reactive protein and decreased anti-inflammatory molecule, adiponectin [33]. This low-grade inflammation, which has been associated with an increased risk for atherosclerotic disease and diabetes, may provide a mechanism for the increased risk of these conditions experienced by individuals who have the metabolic syndrome [34]. The potential role of RAGE in the metabolic syndrome was recently shown by a link between a polymorphism of the RAGE gene and IR. Among the RAGE ligands, AGE intake has been shown to be associated with IR and atherosclerosis in mouse models [35]. Several metabolic components well established as risk factors for cardiovascular diseases have also been shown to be associated with altered plasma esRAGE levels. It was reported that plasma esRAGE levels are decreased in individuals with metabolic syndrome and are correlated inversely with several components of metabolic syndrome including BMI, blood pressures, IR index, fasting plasma glucose, serum triacylglycerol, and lower HDLc levels [7]. In the current study, it was found that there was a significant negative correlation between serum esRAGE and each of FBG, systolic and diastolic blood pressure, serum triglyceride, serum Tchol, and serum LDLc. This is in agreement with the results obtained by others [4],[7],[17]. Stepwise multiple regression analysis was carried out in patients to examine whether the relation of plasma esRAGE with components of the metabolic syndrome is independent of other clinical factors. The factors associated significantly with plasma esRAGE in coefficient analyses were included as variables. Stepwise regression analysis showed that systolic blood pressure, serum triglyceride, Tchol, LDLc, and HDLc were the independent factors associated significantly with plasma esRAGE levels. This result is in agreement with that obtained by Koyama et al. [7], who concluded that the association of plasma esRAGE with components of metabolic syndrome or atherosclerosis may be linked to inflammation-modulatory roles of esRAGE. This association raises the possibility that esRAGE may play a role in arterial stiffening and its complications. Also, it supports the decoy function of esRAGE and its beneficial effect in capturing AGEs. The results may represent an avenue for more future studies on the clinical use of sRAGE as an effective medication for various conditions including type II diabetes and vascular diseases associated with diabetes.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
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